PROJECT SUMMARY/ABSTRACT This application describes two programs of research aimed at improving the efficiency and selectivity of chemical synthesis relevant to small molecule drug discovery efforts. The primary objective of the first program is to identify a new catalytic system that can initiate a cascade of ring forming reactions from polyunsaturated precursors. Nature constructs all terpenoids by initiating cationic cascade cyclizations under exquisite control of stereochemistry. Chemical analogs of this natural process that deliver high levels of stereocontrol have only recently emerged. However, they are limited in their ability to in- troduce the requisite functionality needed for the production of the final product. By harnessing the potential of chiral Lewis base catalysis, enantiomerically enriched thiiranium ions will initiate the cationic cascade by spon- taneously engaging the proximal double bonds in the substrate. The resulting polycyclic product will thus con- tain a thioether functional group at a strategically crucial position that will allow subsequent manipulations. The primary objective of second program is the creation of a small library of stereodefined, functionalized, three-dimensional building blocks that can be introduced as plugins for the optimization and diversification of small molecule candidates in drug discovery programs. One of the major problems facing the research and discovery efforts in the pharmaceutical industry is the mismatch between the chemical characteristics of avail- able screening libraries and the kinds of characteristics needed to intervene by association and interaction with biomolecular targets. This problem arises from the lack of robust methods that reliably and predictably install three dimensional carbon centers bearing appropriate functionality in both manual and automated platforms. By systematic examination of the stereochemical outcome of the coupling of small, stereodefined boron- containing building blocks and a rigorous understanding of the mechanisms of their introduction, this program will provide the medicinal chemistry community with reagents that constitute ?stereocenters in a bottle?. The Administrative Supplement is requested to purchase a Supercritical Fluid Chromatograph (SFC) to en- able the high throughput analysis of chiral, enantiomerically enriched products that will be generated in all phases of both primary objectives. My group has used chiral stationary phase SFC since 1998 and were among the very first academic laboratories to adopt this high precision analytical method. All of our projects require this instrument to be running continuously (automated injection mode). Since 1998 we have purchased three SFC units and the most recent one, an Aurora/Agilent unit has now failed requiring the purchase of a new pump module which is prohibitively expensive given the age of the instrument. The quote from Agilent provides a more robust instrument with the capability of running continuously as well as providing semi-preparative ca- pabilities. This instrument is absolutely mission critical for the success of the projects outlined above. This re- quest was not included in the original application as the instrument was functioning until March 2018.